Biomarkers and Mechanisms of Stress Pathophysiology in Early Schizophrenia

摘要 压力是导致精神障碍的主要因素，包括 精神分裂症先前的研究显示下丘脑可能有异常- 垂体-肾上腺（HPA）轴在精神分裂症，有证据表明，精神分裂症患者显示 皮质醇的异常水平，主要的压力荷尔蒙，对压力的反应。皮质醇启动 身体对压力的反应，但也抑制炎症活动，可能是有害的， 健康越来越多的证据表明，精神分裂症的特征是一种低水平的 炎症，虽然这种炎症的起源和后果是未知的。两 皮质醇和炎症标志物可能对大脑有影响，相反，大脑可能 自上而下控制皮质醇和对压力的免疫反应。K23的设计 临床研究项目，由主要研究者约书亚Chiappelli博士提交，将比较 精神分裂症患者与健康对照者对基于实验室的 压力挑战，包括心理压力源和涉及 暴露在痛苦中皮质醇和IL-6的水平将在之前收集的唾液样本中测量 在这些压力挑战之后，检查精神分裂症患者是否有异常， 皮质醇对炎症的正常抑制。大脑中的谷氨酸水平 同时用磁共振波谱（MRS）和皮质醇和IL-6检查， 测试大脑是否调节了对压力的周边反应。该项目将在 马里兰州精神病学研究中心（MPRC）是马里兰州大学精神病学学院的一部分， 药MPRC经营着几家专门治疗精神分裂症的门诊诊所 患者以及MR成像中心; MPRC的研究计划包括临床前 和临床研究，重点是精神分裂症的原因，过程和治疗。 K23提案还包括一个全面的培训计划，以促进Chiappelli博士的 成为独立的临床研究者。导师将由埃利奥特博士提供 洪，精神分裂症和神经影像学专家;劳拉·罗兰博士， 精神分裂症的磁共振波谱学;列奥纳多托内利博士，一位精神分裂症的专家， 神经免疫学;以及压力和发展专家戴安娜·菲什拜因博士。这个项目 将为R 01进一步研究应激机制提供初步数据 精神分裂症的病理生理学，并将为Chiappelli博士提供必要的教育 和技能发展，以领导作为独立临床的进一步转化研究 调查员

Abstract Stress is a major factor contributing to development of psychiatric disorders, including schizophrenia. Previous studies have revealed possible abnormalities in the hypothalamic- pituitary-adrenal (HPA) axis in schizophrenia, with evidence that schizophrenia patients show abnormal levels of cortisol, the main stress hormone, in response to stress . Cortisol primes the body to respond to stress, but also suppresses inflammatory activity that could be detrimental to health. There is increasing evidence that schizophrenia is characterized by a state of low-grade inflammation, though the origin and consequences of this inflammation are unknown. Both cortisol and inflammatory markers may have effects on the brain, and conversely, the brain may exert top-down control over cortisol and immune responses to stress. This K23 mentored clinical research project, submitted by Principal Investigator Dr. Joshua Chiappelli, will compare individuals with schizophrenia to healthy controls in how they respond to laboratory based stressful challenges, including a psychological stressor and a somatic stressor that involves exposure to pain. Levels of cortisol and IL-6 will be measured in saliva samples collected before and after these stress challenges to examine if schizophrenia patients have an abnormality in the normal suppression of inflammation by cortisol. Levels of glutamate in the brain will be examined with magnetic resonance spectroscopy (MRS) concurrently with cortisol and IL-6 to test if peripheral responses to stress are modulated by the brain. This project will take place at the Maryland Psychiatric Research Center (MPRC), part of the University of Maryland School of Medicine. The MPRC operates several outpatient clinics specializing in care of schizophrenia patients as well as a MR imaging center; the research programs of the MPRC include preclinical and clinical research studies focusing on the causes, course, and treatment of schizophrenia. The K23 proposal also includes a comprehensive training plan to facilitate Dr. Chiappelli’s development into an independent clinical researcher. Mentorship will be provided by Dr. Elliot Hong, an expert in schizophrenia and neuroimaging; Dr. Laura Rowland, an expert in use of magnetic resonance spectroscopy in schizophrenia; Dr. Leonardo Tonelli, an expert on neuroimmunology; and Dr. Diana Fishbein, an expert on stress and development. This project will provide preliminary data for further R01 investigations into the mechanisms of stress pathophysiology in schizophrenia and will provide Dr. Chiappelli with the necessary education and skill development to lead further translational studies as an independent clinical investigator.